Cromolyn esters and uses thereof

ABSTRACT

Described herein are compounds and methods of treating or imaging a disease or disorder, such as Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, ischemic stroke, and prion disease, comprising administering a therapeutically effective amount of a cromolyn ester.

RELATED APPLICATION

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 62/777,456, filed Dec. 10, 2018, which is herebyincorporated by reference in its entirety.

GOVERNMENT SUPPORT

This invention was made with government support under grant numberP41EB022544 TDR3 awarded by The National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

Cromolyn, also referred to as cromoglicic acid, is traditionallydescribed as a mast cell stabilizer since it works by preventing therelease of mediators such as histamine and cytokines from mast cellsthereby stabilizing inflammatory cells. Prevention of mediator releaseis thought to result from indirect blockade of the entry of calcium ionsinto the membrane of sensitized mast cells. Cromolyn has also been shownto inhibit the movement of other inflammatory cells such as neutrophils,eosinophils, and monocytes.

Cromolyn is commonly marketed as the sodium salt sodium cromoglicate orcromolyn sodium for the treatment of asthma and various allergies.Typically, cromolyn is administered as a nasal spray or as a nebulizedsolution with an inhaler. However, cromolyn is a highly polar molecule,and thus suffers from poor bioavailability even when administered byinhalation. Moreover, many patients (especially children and theelderly) find inhalers difficult to use, and poor inhalation techniquecan affect the amount of drug reaching the lungs and response totherapy.

Therefore, there is a need for the development of orally availablecromolyn analogs.

SUMMARY OF INVENTION

Provided herein are compounds, compositions and methods useful in thetreatment and/or prevention of disease. In some embodiments, the methodscomprise administering a compound disclosed herein or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the methods furthercomprise administering a pharmaceutically acceptable carrier.

In one aspect, the compounds disclosed herein have a structure ofFormula I

wherein

R¹ is hydroxyl, ¹⁸F, or F; and

R² is independently alkyl,

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating or preventinga disease or condition comprising administering a compound having thestructure of Formula I

wherein

R¹ is hydroxyl, ¹⁸F, or F; and

R² is independently alkyl,

or a pharmaceutically acceptable salt thereof,wherein the disease or condition is Alzheimer's disease, Huntington'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, stroke,ischemic stroke, prion disease, a head injury, a traumatic brain injury,dementia, an infection, atherosclerosis, or asthma. In some embodiments,the method further comprises administering a pharmaceutically acceptablecarrier. In some embodiments, the compound is administered orally. Incertain embodiments, the compound is in a solid dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot showing the time activity curve (TAC) for compound 6from a brain positron emission tomography (PET) imaging study.

FIG. 2 is a plot showing the time activity curve (TAC) for compound 5from a brain positron emission tomography (PET) imaging study.

FIG. 3 is a plot showing the time activity curve (TAC) for ¹⁸F-Cromolyn(diacid) from a brain positron emission tomography (PET) imaging study.

FIG. 4 shows the inhibition of Δβ 42 aggregation using the thioflavin Tassay with compound 2, ¹⁸F-Cromolyn (diacid), and Cromolyn.

DETAILED DESCRIPTION

In certain aspects, provided herein are cromolyn esters, compositionsand methods related to the treatment and/or prevention of a disease orcondition (e.g., Alzheimer's disease, Huntington's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, stroke, ischemic stroke, priondisease, a head injury, a traumatic brain injury, dementia, aninfection, atherosclerosis, asthma).

I. Compounds

In certain embodiments, provided herein are compounds having thestructure of Formula I

whereinR¹ is hydroxyl, ¹⁸F, or F; andR² is alkyl,or a pharmaceutically acceptable salt thereof. In some embodiments, R²is ethyl, In some embodiments, R² is t-butyl.

In certain embodiments, provided herein are compounds having thestructure of Formula I

whereinR¹ is hydroxyl, ¹⁸F, or F; andR² is alkyl. In some embodiments, R² is ethyl, In some embodiments, R²is t-butyl.

In certain embodiments, the compound is selected from the compoundsidentified in Table 1 or a pharmaceutically acceptable salt thereof. Incertain embodiments, the compound is selected from the compoundsidentified in Table 1.

TABLE 1 Compound Structure 1

2

3

4

5

6

II. Pharmaceutical Compositions

In certain embodiments, the present invention provides pharmaceuticalcompositions comprising a compound disclosed herein and apharmaceutically acceptable carrier.

The compositions and methods of the present invention may be utilized totreat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound of the invention and apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known in the art and include, for example, aqueoussolutions such as water or physiologically buffered saline or othersolvents or vehicles such as glycols, glycerol, oils such as olive oil,or injectable organic esters. In a preferred embodiment, when suchpharmaceutical compositions are for human administration, particularlyfor invasive routes of administration (i.e., routes, such as injectionor implantation, that circumvent transport or diffusion through anepithelial barrier), the aqueous solution is pyrogen-free, orsubstantially pyrogen-free. The excipients can be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition can be indosage unit form such as tablet, capsule (including sprinkle capsule andgelatin capsule), granule, lyophile for reconstitution, powder,solution, syrup, suppository, injection or the like. The composition canalso be present in a transdermal delivery system, e.g., a skin patch.The composition can also be present in a solution suitable for topicaladministration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a self-emulsifying drug deliverysystem or a self-microemulsifying drug delivery system. Thepharmaceutical composition (preparation) also can be a liposome or otherpolymer matrix, which can have incorporated therein, for example, acompound of the invention. Liposomes, for example, which comprisephospholipids or other lipids, are nontoxic, physiologically acceptableand metabolizable carriers that are relatively simple to make andadminister.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The compound may also be formulated for inhalation. In certainembodiments, a compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, aswell as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the patient's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the invention. A larger total dose canbe delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

An effective amount of the composition may be administered in a singledose per day or in fractional doses over the day, for example two tothree times a day. By way of example, the administration of acomposition according to the invention may be performed at a rate, forexample, of 3 times a day or more, generally over a prolonged period ofat least a week, 2 weeks, 3 weeks, 4 weeks, or even 4 to 15 weeks,optionally comprising one or more periods of stoppage or being repeatedafter a period of stoppage.

In certain embodiments, the compound may be administered at a dosebetween 1 mg and 1,500 mg per day, such as between 5 mg and 1,300 mg perday, such as between 10 mg and 900 mg per day, such as between 20 mg and600 mg per day, such as between 40 mg and 300 mg per day, such asbetween 150 mg and 350 mg per day, such as between 40 and 150 mg perday, such as between 25 mg and 150 mg per day, such as between 2.5 mgand 150 mg per day, such as between 20 mg and 80 mg per day, or such asbetween 1 mg and 30 mg per day. In certain embodiments, the compound maybe administered at a dose of 1,300 mg/day, 900 mg/day, 600 mg/day, 350mg/day, 300 mg/day, 250 mg/day, 200 mg/day, 150 mg/day, 80 mg/day, 75mg/day, 60 mg/day, 40 mg/day, 30 mg/day, 20 mg/day, 15 mg/day, 10mg/day, 5 mg/day, or 2.5 mg/day.

Dosages for compounds may be as low as 5 ng/d. In certain embodiments,about 10 ng/day, about 15 ng/day, about 20 ng/day, about 25 ng/day,about 30 ng/day, about 35 ng/day, about 40 ng/day, about 45 ng/day,about 50 ng/day, about 60 ng/day, about 70 ng/day, about 80 ng/day,about 90 ng/day, about 100 ng/day, about 200 ng/day, about 300 ng/day,about 400 ng/day, about 500 ng/day, about 600 ng/day, about 700 ng/day,about 800 ng/day, about 900 ng/day, about 1 μg/day, about 2 μg/day,about 3 μg/day, about 4 μg/day, about 5 μg/day, about 10 μg/day, about15 μg/day, about 20 μg/day, about 30 μg/day, about 40 μg/day, about 50μg/day, about 60 μg/day, about 70 μg/day, about 80 μg/day, about 90μg/day, about 100 μg/day, about 200 μg/day, about 300 μg/day, about 400μg/day about 500 μg/day, about 600 μg/day, about 700 μg/day, about 800μg/day, about 900 μg/day, about 1 mg/day, about 2 mg/day, about 3mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day or about 50mg/day of the compound is administered.

Dosage ranges for active agents may be from 5 ng/d to 100 mg/day. Incertain embodiments, dosage ranges for active agents may be from about 5ng/day to about 10 ng/day, about 15 ng/day, about 20 ng/day, about 25ng/day, about 30 ng/day, about 35 ng/day, about 40 ng/day, about 45ng/day, about 50 ng/day, about 60 ng/day, about 70 ng/day, about 80ng/day, about 90 ng/day, about 100 ng/day, about 200 ng/day, about 300ng/day, about 400 ng/day, about 500 ng/day, about 600 ng/day, about 700ng/day, about 800 ng/day, or about 900 ng/day. In certain embodiments,dosage ranges for compounds may be from about 1μg/day to about 2 μg/day,about 3 μg/day, about 4 μg/day, about 5 μg/day, about 10 μg/day, about15 μg/day, about 20 μg/day, about 30 μg/day, about 40 μg/day, about 50μg/day, about 60 μg/day, about 70 μg/day, about 80 μg/day, about 90μg/day, about 100 μg/day, about 200 μg/day, about 300 μg/day, about 400μg/day about 500 μg/day, about 600 μg/day, about 700 μg/day, about 800μg/day, or about 900 μg/day. In certain embodiments, dosage ranges foractive agents may be from about 1 mg/day to about 2 mg/day, about 3mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800mg/day, or about 900 mg/day.

In certain embodiments, the compounds are administered in pM or nMconcentrations. In certain embodiments, the compounds are administeredin about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 20 pM, about30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM,about 90 pM, about 100 pM, about 200 pM, about 300 pM, about 400 pM,about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM,about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM,about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 nM, about 30nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM,about 90 nM, about 100 nM, about 300 nM, about 400 nM, about 500 nM,about 600 nM, about 700 nM, about 800 nM, or about 900 nM,concentrations.

This invention includes the use of pharmaceutically acceptable salts ofcompounds of the invention in the compositions and methods of thepresent invention. The term “pharmaceutically acceptable salt” as usedherein includes salts derived from inorganic or organic acids including,for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric,glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic,malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, andother acids. Pharmaceutically acceptable salt forms can include formswherein the ratio of molecules comprising the salt is not 1:1. Forexample, the salt may comprise more than one inorganic or organic acidmolecule per molecule of base, such as two hydrochloric acid moleculesper molecule of a compound. As another example, the salt may compriseless than one inorganic or organic acid molecule per molecule of base,such as two molecules of a compound per molecule of tartaric acid.

In certain embodiments, contemplated salts of the invention include, butare not limited to, L-arginine, benenthamine, benzathine, betaine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)ethanol, ethanolamine, ethylenediamine,N-methylglucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium,4-(2-hydroxyethyl)morpholine, piperazine, potassium,1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine,and zinc salts. In certain embodiments, contemplated salts of theinvention include, but are not limited to, Na, Ca, K, Mg, Zn or othermetal salts. In further embodiments, contemplated salts of the inventioninclude, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkylammonium salts.

The pharmaceutically acceptable salts can also exist as varioussolvates, such as with water, methanol, ethanol, dimethylformamide, andthe like. Mixtures of such solvates can also be prepared. The source ofsuch solvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent.

As one of skill in the art will appreciate, compositions of the presentinvention, not having adverse effects upon administration to a subject,may be administered daily to the subject.

Preferred embodiments of this invention are described herein. Of course,variations, changes, modifications and substitution of equivalents ofthose preferred embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations, changes,modifications and substitution of equivalents as appropriate, and theinventors intend for the invention to be practiced otherwise thanspecifically described herein. Those of skill in the art will readilyrecognize a variety of non-critical parameters that could be changed,altered or modified to yield essentially similar results. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

While each of the elements of the present invention is described hereinas containing multiple embodiments, it should be understood that, unlessindicated otherwise, each of the embodiments of a given element of thepresent invention is capable of being used with each of the embodimentsof the other elements of the present invention and each such use isintended to form a distinct embodiment of the present invention.

III. Methods

In some embodiments, provided herein is a method for treating a diseaseor condition in a subject in need thereof, comprising administering tothe subject a compound (e.g., a compound of Formula I) or a compositiondisclosed herein.

In some embodiments, the disease or condition is selected fromAlzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), stroke,ischemic stroke, prion disease, Huntington's disease, Parkinson'sdisease, head injury, traumatic brain injury (TBI), dementia, infection,atherosclerosis, asthma, and amyloidosis-associated condition.

An “amyloidosis-associated condition” is a disease that is associatedwith amyloid deposition and can include but not be limited toAlzheimer's Disease, idiopathetic myeloma, amyloid polyneuropathy,amyloid cardiomyopathy, systemic senile amyloidosis, amyloidpolyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down'ssyndrome, Scrapie, medullary carcinoma of the thyroid, isolated atrialamyloid, ^(β) ₂-microglobulin amyloid in dialysis patients, inclusionbody myositis, β₂-amyloid deposits in muscle wasting disease, and Isletsof Langerhans diabetes Type I1 insulinoma. Type 2 diabetes mellitus,hereditary cerebral hemorrhage amyloidosis (Dutch), amyloid A(reactive), secondary amyloidosis, familial Mediterranean fever,familial amyloid nephropathy with urticaria and deafness (Muckle-wellsSyndrome), amyloid lambda L-chain or amyloid kappa L-chain (idiopathic,myeloma or macroglobulinemia-associated) A beta 2M (chronichemodialysis), ATTR (familial amyloid polyneuropathy (Portuguese,Japanese, Swedish)), familial amyloid cardiomyopathy (Danish), isolatedcardiac amyloid, systemic senile amyloidoses, AIAPP or amylininsulinoma, atrial naturetic factor (isolated atrial amyloid),procalcitonin (medullary carcinoma of the thyroid), gelsolin (familialamyloidosis (Finnish)), cystatin C (hereditary cerebral hemorrhage withamyloidosis (Icelandic)), AApo-A-1 (familial amyloidoticpolyneuropathy-Iowa), AApo-A-II (accelerated senescence in mice), headinjuries (traumatic brain injury), dementia, fibrinogen-associatedamyloid; and Asor or Pr P-27 (scrapie, Creutzfeld Jacob disease,Gertsmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis)or in cases of persons who are homozygous for the apolipoprotein E4allele, and the condition associated with homozygosity for theapolipoprotein E4 allele or Huntington's disease.

“Amyloidosis” is a condition characterized by the accumulation ofvarious insoluble, fibrillar proteins in the tissues of a patient. Anamyloid deposit is formed by the aggregation of amyloid proteins,followed by the further combination of aggregates and/or amyloidproteins.

Many forms of amyloidosis exist, and the disease can be classified intofour groups: primary amyloidosis, secondary amyloidosis, hereditaryamyloidosis, and amyloidosis associated with normal aging. Primaryamyloidosis (light chain amyloidosis) occurs with abnormalities ofplasma cells, and some people with primary amyloidosis also havemultiple myeloma (cancer of the plasma cells). Typical sites of amyloidbuildup in primary amyloidosis are the heart, lungs, skin, tongue,thyroid gland, intestines, liver, kidneys, and blood vessels. Secondaryamyloidosis may develop in response to various diseases that causepersistent infection or inflammation, such as tuberculosis, rheumatoidarthritis, and familial Mediterranean fever. Typical sites of amyloidbuildup in secondary amyloidosis are the spleen, liver, kidneys, adrenalglands, and lymph nodes. Hereditary amyloidosis has been noted in somefamilies, particularly those from Portugal, Sweden, and Japan. Theamyloid-producing defect occurs because of mutations in specificproteins in the blood. Typical sites for amyloid buildup in hereditaryamyloidosis are the nerves, heart, blood vessels, and kidneys.

In some embodiments of the methods described herein, the compound isadministered orally. In some embodiments of the methods describedherein, the compound is in a solid dosage form.

IV. Definitions

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention are to be construed to cover both thesingular and the plural, unless otherwise indicated herein or clearlycontradicted by context. All methods described herein can be performedin any suitable order unless otherwise indicated herein or otherwiseclearly contradicted by context. The use of any and all examples, orexemplary language (e.g., “such as”) provided herein is intended merelyto better illuminate the present invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the present specification should be construed as indicating anyunclaimed element is essential to the practice of the invention.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group. An alkyl group with two openvalences is sometimes referred to as an alkylene group, such asmethylene, ethylene, propylene and the like.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat the moieties substituted on the hydrocarbon chain can themselves besubstituted, if appropriate. For instance, the substituents of asubstituted alkyl may include substituted and unsubstituted forms ofamino, azido, imino, amido, phosphoryl (including phosphonate andphosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl andsulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls(including ketones, aldehydes, carboxylates, and esters), —CF₃, —CN andthe like. Exemplary substituted alkyls are described below. Cycloalkylscan be further substituted with alkyls, alkenyls, alkoxys, alkylthios,aminoalkyls, carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively. As applied toheteroalkyls, “C_(x-y)” indicates that the group contains from x to ycarbons and heteroatoms in the chain. As applied to carbocyclicstructures, such as aryl and cycloalkyl groups, “C_(x-y)” indicates thatthe ring comprises x to y carbon atoms. As applied to heterocyclicstructures, such as heteroaryl and heterocyclyl groups, “C_(x-y)”indicates that the ring contains from x to y carbons and heteroatoms. Asapplied to groups, such as aralkyl and heterocyclylalkyl groups, thathave both ring and chain components, “C_(x-y)” indicates that the ringand the chain together contain from x to y carbon atoms and, asappropriate heteroatoms.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represent a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a hetaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent. In analogy with alkyl groups,heteroalkyl groups with two open valences are sometimes referred to asheteroalkylene groups. Preferably, the heteroatoms in heteroalkyl groupsare selected from O and N.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include, for example, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, andpyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and “heterocyclic” also include polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocyclyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

As used herein, “mitigating” means reducing the negative effects causedby exposure to ionizing radiation, relative to a cell, organ, tissue, ororganism exposed to the same level of radiation for the same amount oftime, but untreated.

As used herein, a “therapeutically effective amount” is an amountsufficient to mitigate the effects of the ionizing radiation.

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7. When a polycyclic substituent isattached through an aryl or heteroaryl ring, that substituent may bereferred to herein as an aryl or heteroaryl group, while if thepolycyclic substituent is attached through a cycloalkyl or heterocyclylgroup, that substituent may be referred to herein as a cycloalkyl orheterocyclyl group. By way of example, a1,2,3,4-tetrahydronaphthalen-1-yl group would be a cycloalkyl group,while a 1,2,3,4-tetrahydronaphthalen-5-yl group would be an aryl group.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the moiety. It willbe understood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds.

In a broad aspect, the permissible substituents include acyclic andcyclic, branched and unbranched, carbocyclic and heterocyclic, aromaticand non-aromatic substituents of organic compounds. The permissiblesubstituents can be one or more and the same or different forappropriate organic compounds. For purposes of this invention, theheteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valences of the heteroatoms. Substituents can include anysubstituents described herein, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, asulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, asulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic orheteroaromatic moiety. It will be understood by those skilled in the artthat substituents can themselves be substituted, if appropriate. Unlessspecifically stated as “unsubstituted,” references to chemical moietiesherein are understood to include substituted variants. For example,reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

As used herein, the term “administering” means the actual physicalintroduction of a composition into or onto (as appropriate) a subject.Any and all methods of introducing the composition into subject arecontemplated according to the invention; the method is not dependent onany particular means of introduction and is not to be so construed.Means of introduction are well known to those skilled in the art, andalso are exemplified herein.

As used herein, the terms “effective amount”, “effective dose”,“sufficient amount”, “amount effective to”, “therapeutically effectiveamount” or grammatical equivalents thereof mean a dosage sufficient toproduce a desired result, to ameliorate, or in some manner, reduce asymptom or stop or reverse progression of a condition and provide eithera subjective relief of a symptom(s) or an objectively identifiableimprovement as noted by a clinician or other qualified observer.Amelioration of a symptom of a particular condition by administration ofa pharmaceutical composition described herein refers to any lessening,whether permanent or

temporary, lasting, or transitory, that can be associated with theadministration of the pharmaceutical composition.

As used herein, the term “pharmaceutically acceptable” refers tocompositions that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction when administered to asubject, preferably a human subject. Preferably, as used herein, theterm “pharmaceutically acceptable” means approved by a regulatory agencyof a federal or state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia

for use in animals, and more particularly in humans.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample.

A “subject,” as used herein, can be any mammal. For example, a subjectcan be a human, a non-human primate (e.g., monkey, baboon, orchimpanzee), a horse, a cow, a pig, a sheep, a goat, a dog, a cat, arabbit, a guinea pig, a gerbil, a hamster, a rat, or a mouse. In someembodiments, the subject is an infant (e.g., a human infant). In someembodiments, the subject is a human.

The term “treating” is art-recognized and includes administration to thehost of one or more of the subject compositions, e.g., to diminish,ameliorate, or stabilize the existing unwanted condition or side effectsthereof.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1—Synthesis of5,5′-[(2-Hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid Diethyl Ester

Briefly, a suspension of cromolyn sodium salt (1.0 g, 2 mmol) in EtOH(100 mL) and con. HCl (1 mL) was heated in a sealed reactor tube for 24h at 100° C. The white solid was dissolved to give a clear colorlesssolution while hot. It was allowed to cool to room temperature andNaHCO₃ (1.0 g) was added. After stirring for 30 min at 25° C., solventwas removed by roto-evaporation. Chromatography on silica gel of thecrude material using 5:95 methanol/methylene chloride yielded thediethyl ester (0.8 g, 76% yield); mp 154-156° C.; ¹H NMR (CDCl₃, 300MHz) δ 1.42 (t, 3H, J=7.1 Hz, CH₃), 2.73 (br s, 1H, OH), 4.44 (q, 4H,J=7.1 Hz, 2OCH₂CH₃), 4.32-4.59 (m, 5H, CHOH, 2OCH₂), 6.80 (s, 2H,2vinyl-H), 6.99 (d, 2H, J=8.24 Hz, 2Aro-H), 7.12 (d, 2H, J=8.24 Hz,2Aro-H), 7.17 (d, 2H, J=8.24 Hz, 2Aro-H), 7.71 (t, 2H, J=8.24 2Aro-H).

Example 2—Synthesis of5,5′-[(2-Fluoro-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid Diethyl Ester a) 3-Bis(4-methylbezenesulfonate)-2-fluoropropanediol

A solution of 1,3-bis(4-methylbezenesulfonate propanetriol (2.7 g, 6.78mmol) in methylene chloride (20 mL) at 0-5° C. was treated with DAST(2.18 g, 13.6 mmol). The mixture was stirred at 0-5° C. for 30 thenallowed to warm to 25° C. and stirred for 16 hr. The mixture was pouredinto a sat'd sodium bicarbonate solution (30 mL) and layers separated.The methylene chloride layer dried (sodium sulfate). After solventremoval, the crude material was chromatographed on silica gel (methylenechloride) to yield 0.82 g (30%) of a solid; mp 99-102° C.; ¹H NMR(CDCl₃), δ 2.5 (s, 6H, CH₃), 4.15 (dd, 4H, J=12.3, 4.6 Hz, CH₂, 4.8 (dq,1H, J=47, 4.6, CHF), 7.45 (d, 4H, J=8.1 Hz, Aro-H), 7.75 (d, 4H, J=8.4Hz, Aro-H).

b)5,5′-(2-fluoropropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxylicAcid)

1,3-Bis(2-acetyl-3-hydroxyphenoxy)-2-fluoropropane

A mixture of 3-bis(4-methylbezenesulfonate)-2-fluoropropanediol (1.0,2.5 mmol), 2,6-dihydroxyacetophenone (0.76 g, 5.0 mmol) and potassiumcarbonate (0.69 g) in acetonitrile (40 mL) was heated under reflux for16 hr. The mixture was filtered and the filtrate was evaporated. Thecrude material was chromatographed on silica gel (acetonitrile/methylenechloride 5:95) to yield 0.57 g (40%) of product; mp 162-165° C.; ¹H NMR(d6-DMSO), δ 2.5 (s, 6H, 2CH₃), 4.38 (m, 4H, 2CH₂), 5.22 (br d 1H, J=49Hz, CHF), 6.45 (m, 4H, 4Aro-H), 7.28 (t, 2H, J=4.55 Hz, 2Aro-H).

c)5,5′-[(2-Fluoro-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid Diethyl Ester

A mixture of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-fluoropropane (200 mg,0.52 mmol) and ethyl oxalate (2 mL) was added to a solution of sodiumethoxide (87 mg Na) in ethanol (10 mL) and benzene (10 mL). The mixturewas heated at reflux for 16 hr, cooled and diluted with ether (50 mL).The precipitated sodium salt was filtered, washed with ether and dried.It was then dissolved in water and acidified with 10% HCl to obtain asticky solid. The solid was refluxed in ethanol (20 mL) with a catalyticamount of 36% HCL for 1 hr. The mixture was poured into 50 mL of waterand extracted twice with methylene chloride (50 mL). The extracts werecombined and dried. After solvent removal, the crude material waschromatographed on silica gel (acetonitrile/methylene chloride 10:90) toyield 0.12 g (45%) of product; mp 166-170° C.; ¹H NMR (CDCl₃), δ 1.42(t, 6H, J=7.14 Hz, 2CH₃), 4.58 (q, 4H, J=7.14 Hz 2CH₂), 4.65 (m, 4H,2CH₂), 5.35 (dq, 1H, J=46 Hz, J=4.4 HZ, CHF), 6.90 (s, 2H, vinyl-H),6.95 (d, 2H, J=8.24 Hz, 2Aro-H), 7.13 (d, 2H, J=8.24 Hz, 2Aro-H), 7.17(d, 2H, J=8.24 Hz, 2Aro-H) 7.6 (t, 2H, J=8.24 2Aro-H).

Alternatively, a solution of1,3-bis[tolylsulfonyl)oxy]-2-[(trifluoromethyl)sulfonyl]oxy-propane (9mg) in acetonitrile (0.4 mL) was added to a vial containing driedK¹⁸F/Kryptofix complex (3 mg K₂CO₃, 7 mg Kryptofix) and fluorination wasperformed at 80° C. for 10 min. The resultant 2-[¹⁸F]fluoropropane1,3-ditosylate solution was passed through a silica gel SepPak usingmethylene chloride into a vial containing K₂CO₃ (10 mg) and ethyl5-hydroxy-4-oxo-4H-chromene-2-carboxylate (10 mg). After solventremoval, DMSO was added and the mixture was heated for 10 min at 130° C.After addition of 1 mL of 5% HCl, followed by 2 mL of 50/50 acetonitrile0.1M ammonium formate and filtering (Millex-LCR 0.45 m), F-18 cromolyndiester was purified by HPLC (C18, 50:50 acetonitrile/0.1M ammoniumformate). Synthesis was complete within 90 min with a yield of 20%(corrected for EOB) and chemical purity of greater than 95%.

Example 3—Synthesis of5,5′-[(2-Hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid di-tert-butyl Ester

Cromolyn disodium salt (5 g) dissolved in water (100 mL) was acidifiedwith 10% HCl and the ensuing diacid precipitate was filtered and dried.A suspension of cromolyn diacid powder (1.0 g, 2.1 mmol) in toluene (80mL) was heated to reflux. N,N-dimethylformamide di-tert-butyl acetal(4.3 g, 21 mmol) was added dropwise over 4 hours and the mixture wasrefluxed overnight. The reaction mixture was decanted to remove solidsand the solvent was evaporated in vacuo at 50° C. Chromatography onsilica gel of the crude material using 65:30:5 hexane/ethylacetate/methanol yielded the di-tert-butyl ester (0.37 g, 30% yield); mp147-149° C.; ¹H NMR (CDCl₃, 400 MHz) δ 1.57 (s, 9H, CH₃), 2.73 (br s,1H, OH), 4.32-4.59 (m, 4H, 20CH₂), 5.35 (br d, 1H, J=46 Hz, CHF), 6.87(s, 2H, 2vinyl-H), 6.93 (d, 2H, J=8.24 Hz, 2Aro-H), 7.12 (d, 2H, J=8.24Hz, 2Aro-H), 7.14 (d, 2H, J=8.24 Hz, 2Aro-H), 7.57 (t, 2H, J=8.242Aro-H). HPLC analysis was performed on a Phenomenex Luna C18 column(250 mm×4.60 mm) using 60:40 acetonitrile/0.1M ammonium formate (1mL/min) as the mobile phase (Rt=14 min).

Example 4—Synthesis of5,5′-[(2-Fluoro-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid di-tert-butyl Ester

An analogous procedure described above in Example 3 for5,5′-[(2-hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicacid di-tert-butyl ester was used. Chromatography on silica gel of thecrude material using 70:30 hexane/ethyl acetate yielded thedi-tert-butyl ester (0.47 g, 39% yield); ¹H NMR (CDCl₃, 400 MHz) δ 1.57(s, 9H, CH₃), 2.73 (br s, 1H, OH), 4.32-4.59 (m, 4H, 20CH₂), 5.35 (dq,1H, J=46 Hz, J=4.4 HZ, CHF), 6.87 (s, 2H, 2vinyl-H), 6.93 (d, 2H, J=8.24Hz, 2Aro-H), 7.12 (d, 2H, J=8.24 Hz, 2Aro-H), 7.14 (d, 2H, J=8.24 Hz,2Aro-H), 7.57 (t, 2H, J=8.24 2Aro-H). HPLC analysis was performed on aPhenomenex Luna C18 column (250 mm×4.60 mm) using 70:30acetonitrile/0.1M ammonium formate (1 mL/min) as the mobile phase(Rt=13.2 min).

Example 5—Synthesis of5,5′-[(2-[18F]Fluoro-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-carboxylicAcid di-tert-butyl Ester

The hydroxy cromolyn di-tert-butyl ester of Example 3 (0.5 g 0.86 mg),p-toluenesulfonyl chloride (0.2 g, 1.76 mmol), and 10 mg of DMAP(4-dimethylaminopyridine) in 20 ml of pyridine were stirred at 0-5° C.for 2 hours and then at 25° C. for 16 hrs. The mixture was washed withcold 10% HCl until the aqueous layer was acidified, and then washed with10% NaHCO₃. Chromatography of the crude oil on silica gel usingmethylene chloride:methanol (95:5) gave 0.48 g (76%) of the tosylate ofcromolyn di-tert-butyl ester.

A solution of the tosylate of cromolyn di-tert-butyl ester (5 mg) inDMSO (0.4 mL) was added to a 5-mL vial containing dried K18F/Kryptofixcomplex (3 mg K2CO3, 7 mg Kryptofix). The reaction vial was heated at130° C. for 10 min, cooled to 25° C., and diluted with 1 mL of a mixtureof 10:90 acetonitrile/0.1M ammonium formate. Purification by HPLC (C18,70:30 acetonitrile/0.1M ammonium formate) gave the F-18 cromolyndi-tert-butyl ester. Synthesis was complete within 90 min with a yieldof 40% (corrected for EOB) and chemical purity of greater than 95%.

Example 6—Brain Positron Emission Tomography (PET) Imaging Study

Dynamic PET imaging (GE Discovery MI Scanner) in a rhesus monkey wasperformed with compound 5 (diethyl ester), compound 6 (di-tert-butylester), and ¹⁸F-Cromolyn (diacid).

Monkey imaging for three ¹⁸F-cromolyn analogs showed the order of braintracer penetration was diethyl ester>di-tert-butyl ester>diacid (SeeFIG. 1, FIG. 2, and FIG. 3). Diethyl ester ¹⁸F-cromloyn showed uptake inall regions of the brain with the highest in putamen, grey matter andcerebellum followed by caudate, thalamus and white matter. Uptake wasimmediate, reaching maximum at 2 min (2.3 SUV) and washout was slow, 2SUV at 20 min, 1.5 at 60 min. Brain uptake aligns with lipophilicityvalues where the measure logD for the diethyl ester is 2.5, whereas thedi-tert-butyl is 3.5.

Example 7—Blood Analysis

Arterial blood sampling and radio-metabolite analysis was performed withcompound 5 (diethyl ester), compound 6 (di-tert-butyl ester), and¹⁸F-Cromolyn (diacid). Blood sampling showed ¹⁸F-diacid cromolyn as theonly metabolite at 20 min. The t-butyl ester also metabolized to the¹⁸F-diacid but more slowly. Hydrolysis to the diacid form appears totake place in the blood as evidenced by ex vivo stability tests.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

What is claimed is:
 1. A method of treating or preventing a disease orcondition comprising administering a compound selected from

wherein the disease or condition is a head injury, a traumatic braininjury, dementia, an infection, atherosclerosis, or asthma.
 2. Themethod of claim 1, further comprising administering a pharmaceuticallyacceptable carrier.
 3. The method of claim 1 or 2, wherein the compoundis administered orally.
 4. The method of any one of claims 1 to 3,wherein the compound is in a solid dosage form.
 5. The method of any oneof claims 1 to 4, wherein the compound is


6. The method of any one of claims 1 to 4, wherein the compound is


7. The method of any one of claims 1 to 4, wherein the compound is


8. The method of any one of claims 1 to 7, wherein the method is amethod of treating the disease or condition.
 9. A compound having thefollowing structure:


10. A compound having the following structure:


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and the compound of claim 9 or claim
 10. 12. A methodof treating or preventing a disease or condition comprisingadministering a compound selected from

wherein the disease or condition is Alzheimer's disease, Huntington'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, stroke,ischemic stroke, prion disease, a head injury, a traumatic brain injury,dementia, an infection, atherosclerosis, or asthma.
 13. The method ofclaim 12, further comprising administering a pharmaceutically acceptablecarrier.
 14. The method of claim 12 or 13, wherein the compound isadministered orally.
 15. The method of any one of claims 12 to 14,wherein the compound is in a solid dosage form.
 16. The method of anyone of claims 12 to 15, wherein the compound is


17. The method of any one of claims 12 to 15, wherein the compound is


18. The method of any one of claims 12 to 15, wherein the compound is


19. The method of any one of claims 12 to 18, wherein the method is amethod of treating the disease or condition.
 20. A method of imaging adisease or condition comprising administering a compound selected from

wherein the disease or condition is Alzheimer's disease, Huntington'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, stroke,ischemic stroke, prion disease, a head injury, a traumatic brain injury,dementia, an infection, atherosclerosis, or asthma.
 21. The method ofclaim 20, further comprising administering a pharmaceutically acceptablecarrier.
 22. The method of claim 20 or 21, wherein the compound isadministered orally.
 23. The method of any one of claims 20 to 22,wherein the compound is in a solid dosage form.
 24. A method of imaginga disease or condition comprising administering a compound selected from

wherein the disease or condition is a head injury, a traumatic braininjury, dementia, an infection, atherosclerosis, or asthma.
 25. Themethod of claim 24, further comprising administering a pharmaceuticallyacceptable carrier.
 26. The method of claim 24 or 25, wherein thecompound is administered orally.
 27. The method of any one of claims 24to 26, wherein the compound is in a solid dosage form.